Tetrahydro-imidazo-dibenzo-oxazepines, thiazepines and-diazepines

ABSTRACT

IN WHICH X represents oxygen, sulphur or the group NR4 in which R4 stands for hydrogen or an alkyl group with 1-6 carbon atoms, R1 and R2 represent hydrogen, halogen, hydroxy, an alkyl or alkoxy group with 1-6 carbon atoms, a trifluoromethyl group or an acyloxy group with 1-8 carbon atmos, and R3 means hydrogen, an alkyl group with 1-6 carbon atoms or an aralkyl group with 7-10 carbon atoms AS WELL AS THE ACID ADDITION SALTS AND QUATERNARY AMMONIUM COMPOUNDS THEREOF. These compounds exert a potent antidepressive activity.   The invention relates to compounds of the formula:

United States Patent 1 Van Der Burg 1 Jan. 14, 1975TETRAHYDRO-IMIDAZO-DIBENZO- OXAZEPINES, THIAZEPINES AND-DIAZEPINES [75]Inventor: Willem Jacob Van Der Burg,

l-leesch, Netherlands [73] Assignee: Akzona Incorporated, Asheville,

[22] Filed: Mar. 2, 1973 [21] Appl. No.: 337,323

[30] Foreign Application Priority Data Mar. 7, 1972 Netherlands 7202963[52] US. Cl.... 260/309.7, 260/239 DD, 260/327 B, 260/333, 424/273 [51]Int. Cl C0711 57/02 [58] Field Of Search 260/309.7

[56] 3 References Cited UNITED STATES PATENTS 3,435,042 3/l969 Drukker6t 2117 260/309.6

FOREIGN PATENTS OR APPLICATIONS 1,229,252 4/1971 Great Britain 260/268PC OTHER PUBLICATIONS The Ring Index Supplement 111 to the secondedition, page 256, No. 13084, American Chemical Society, 1965. QD291.P3.

Blattner et al., Chem. Abst., Vol. 76, No. 85721c (1972). QDI.A51

Chemical Abstracts Eighth Collective Index, Volumes 66-75, 1967-1971,Subjects Dibenzobr-Ethanola, page 98798 (1973). QD1.A51.

Chemical Abstracts Eighth Collective Index Volumes 6675 1967-1971,Subjects Glucopelndena, page 156345 (1973). QDLASI. Barton et al., Chem.Abst. Vol. 74, No. 1416342 (1971).OD1.A51.

Primary ExaminerNatalie Trousof Attorney, Agent, or Firm-Francis W.Young; Philip M. Pippenger; Hugo E. Weisberger [57] ABSTRACT Theinvention relates to compounds of theformula:

in which X represents oxygen, sulphur or the groupTETRAHYDRO-IMIDAZO-DIBENZO- OXAZEPINES, THIAZEPINES AND-DIAZEPINES Thepresent invention relates to novel biologically active imidazolidinederivatives. More particularly it relates totetra-hydro-imidazo-dibenzo-oxazepines, -thiazepines and -diazepines.

From the British Pat. No. 1,229,252 compounds are known differing fromthe present compounds in that they contain a piperazine instead of animidazolidine ring. These known piperazine derivatives possessantihistamine and antiserotonine activity.

Surprisingly it has now been found that the present imidazolidinederivatives of the general formula:

in which R, and R hydrogen, hydroxy, halogen, alkyl or alkoxy with 1-6carbon atoms, acyloxy with l-8 carbon atoms, or a trifluoromethyl group,7 R hydrogen, an alkyl group with 1-6 carbon atoms, or an aralkyl groupwith 7-10 carbon atoms, and X oxygen, sulphur or the group NR in whichR, is hydrogen or a lower alkyl group with 1-6 carbon atoms, as well asthe pharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable quaternary ammonium compounds thereof, have a complete othertherapeutical pattern. The compounds according to this invention show,fully contrary to the compounds described in the said British patent, apositive effect in the reserpine antagonism test, which means that theypossess antidepressant activity, whereas the antihistamine andantiserotonine activity of the present compounds may, in general, bedisregarded in comparison with the strong antihistamine and/orantiserotonine activity of the compounds described in the Britishpatent. The compounds according to the invention can be prepared by anymethod commonly used for this type of compounds. They are, however,prepared most conveniently starting from a substance with the generalformula:

or an acid addition salt thereof, in which X, R,, R and R have themeaning indicated above.

These starting compounds are depicted by formula V in the drawings ofsaid British Pat. No. 1,229,252 and their use is described in thespecification thereof at page 2, lines 39-59, disclosing the preparationof piperazine compounds therefrom. The British patent in Sheet 1 of thedrawings discloses the formula of intermediate V to be:

IINlt;

in which R, and R each represent hydrogen, halogen, hydroxyl, acyloxy,lower alkyl, lower alkoxy, or trifluoromethyl; R represents hydrogen,lower alkyl, lower aralkyl, aminoethyl or aminopropyl; and X representsoxygen, sulfur or NR in which R, is lower alkyl. The preparation ofspecific compounds of formula V of said British patent is given in theseveral Examples thereof, and involves starting withortho-amino-diphenyl ether, which is converted toortho-chloracetamido-diphenyl ether by treatment with chloracetylchloride (Example in which Y represents hydrogen (H oxygen or sulphurand i Z, and Z represent the same or different reactive or leavinggroups, or may be together a bivalent reactive group, capable'ofsplitting off together with the hydrogen atoms attached to bothnitrogens of the diamine 11, so forming a compound of the formula:

in which X, Y, R,, R and R have the aforesaid meanings.

In general,- the groups Z, and Z may represent halogen, a substituted orunsubstituted amino group, the group CR or SR in which R representshydrogen, a hydrocarbon radical that may be substituted by hetero atomsor halogen, a R -sulfonyl group, in which R represents a hydrocarbonradical, or Z, and Z together may represent sulphur or oxygen.

If Y represents hydrogen H 2, and Z stand preferably for halogen orhydroxy groups. Reagents III belonging to this type of compounds are,for example, methylenechloride, methylenebromide or methylene diolformaldehyde solution in water or a water containing solvent).

If Y represents oxygen or sulphur the most suitable moieties for Z and Zare halogen, substituted or unsubstituted amino groups, R or SR in whichR represents a hydrocarbon radical that may be substituted by heteroatoms or halogen, or Z and Z together are sulphur (in combination with Ysulphur).

Suitable reagents III belonging to this type of compounds are, forexample, phosgene, thiophosgene, haloformic esters, such asethylchloroformate, esters of carbonic acid such as diethylcarbonate,urea and urea derivatives such as thiourea or N,N'-carbonyl-diimidazole,and carbondisulphide.

Preferably methylene halide or formaldehyde (in water) is used as thereagent III in the present condensation reaction because they yield thedesired final product according to the invention in a direct way.

If a reagent according to the formula III, in which Y represents oxygenor sulphur, is used, the resulting compound must be reduced additionallyto obtain the desired final product. For such a reduction any suitablereducing agent can be used, for example, metal hydrides such as sodiumhydride, lithium aluminium hydride or diborane. Said reduction can alsobe performed catalytically by hydrogenation in the presence of a metalor a metal compound.

If Z and/or Z represent halogen, an agent capable of binding thehydrohalide released in the condensation reaction, such as pyridine,triethylamine, etc., is usually added to the reaction mixture.

The condensation reaction can be performed in any suitable solvent.Where methylene halide is used as the reagent III, special preference isgiven to an aprotic polar solvent such as dimethylsulfoxide, sulfolaneor acetonitril. It is also possible, however, to perform thecondensation exclusively in the reagent, for example, methylenechlorideor a formaldehyde solution, so in the absence of an (additional)solvent. In certain cases, e.g., where urea is used as the reagent III,the condensation can be carried out in a melt.

The acid addition salts of the compounds according to the invention areprepared in the conventional manner by reacting the free base with apharmaceutically acceptable acid such as hydrochloric acid, hydrobromicacid or hydroiodic acid, phosphoric acid, acetic acid, propionic acid,glycollic acid, maleic acid, malonic acid, succinic acid, tartaric acid,citric acid, ascorbic acid, salicylic acid or benzoic acid.

The pharmaceutically acceptable quaternary ammonium compounds, inparticular the lower (1-4 C) alkyl quaternary ammonium compounds, areobtained by reacting the compounds of the general formula I with analkyl halide, for example methyl iodide or methyl bromide.

From the above general formula I it appears that the compounds accordingto the invention possess an asymmetrical carbon. Consequently opticalantipodes are possible, also forming part of this invention. Saidoptical antipodes can be isolated from the racemic mixture in aconventional manner. It is also possible to resolve the racemic startingproduct II into its optical antipodes and to perform the condensationreaction after that, or to resolve an intermediate product obtained inthe synthesis into its optical antipodes.

It is of course possible to introduce or modify the substituents at oneor both phenyl nuclei after the condensation reaction. Thus, forexample, a hydroxy group present can be acylated or converted into analkoxy group, an amino group into a halogen group, a methoxy group intoa hydroxy group, etc.

The substituent (R at the N nitrogen atom can be obtained by alkylatingor aralkylating the unsubstituted nitrogen atom (R H) or by acylatingthe unsubstituted nitrogen atom followed by a reduction of the carbonylmoiety of the N-acyl compound thus obtained.

It is also quite obvious and well-known in the art to convert thealkylor aralkyl substituted N -nitrogen atom (of formula I) into theunsubstituted nitrogen, for example by heating with chloroformic ester,followed by hydrolysis of the compound thus obtained.

The compounds according to the present invention exert as said before,an antidepressant activity. They can be administered both orally andparenterally, preferably in a dosage of between 0.01 and 1 mg per kgbody weight. Mixed with suitable auxiliaries the compounds can becompressed into solid dosage units, such as pills, tablets and coatedtablets. They can also be processed into capsules, mixed withauxiliaries, if desired. By means of suitable liquids the compounds canbe applied as injection preparations in the form of solutions, emulsionsor suspensions.

Compounds which are preferably used in the present invention are:

2,6-dimethyl-l ,2,3, l 3b-tetrahydro-imidazo[ 3 ,4d

dibenzo[b,f](1,4)-oxazepine, Z-methyll ,2,3 l 3b-tetrahydro-imidazo[3,4-dldibenzo[b,f]( 1,4)-oxazepine, 2,12-dimethyl-l ,2,3,13b-tetrahydro-imidazo[3,4-d1- dibenzo[b,f](1,4)-oxazepine.HCl,

Z-methyll 2-chlorol ,2,3, l 3b-tetrahydroimidazo[3,4-d]-dibenzo [b,f]( l,4)-thiazepine, Z-methyl- I 2-trifluoromethyl-l ,2,33b-tetrahydroimidazo[3,4-d] dibenzo[b,f](1,4)-thiazepine,2,9-dimethyl-2,3,9,l 3b-tetrahydro-9H-imidazo[ 3,4-

d]-dibenzo[b,f]( l ,4)-diazepine. The following examples serve toillustrate the invention further.

In the examples the following nomenclature and numbering have been used:

d N 131; z

1,2,3,13b-tetrahydro-9H-imidaz0[3,4-d]-dibenzo[b, i] (1,4)-diazepine.

1 Laminomethyl-10,11-dihydro-dibenzo[b,f] (1,4)-0xazepine.

s g} 6 2 9 H 1 1 l-aminornethyl-lO,11-dihydrodibenzo[b,fl (1,4)-thiazepine.

' 1-aminomethy1-10,11-dihydro-5H-dibenzolb,e] (1,4)-diazepiue.

EXAMPLE I Preparation of 2-methyl-1,2,3,l3b-tetrahydroimidazo[3,4-d]-dibenzo [b,f](1,4)-oxazepine 2 of 11-methy1aminomethy1-10,1l-dihydrodibenzo[b,f]( 1 ,4)-oxazepine are addedto a mixture of 40 ml of ethanol and 15 ml of a 40% solution offormaldehyde in water. The mixture is refluxed for 30 minutes, afterwhich it is evaporated in vacuum to a volume of about 25 ml. An extraquantity of 30 ml of water is added, and the precipitate formed isfiltered and then recrystallised from ethanol. Obtained .in this manner:1.6 g of pure product. Melting point lO2-103C. The tartrate of thiscompound melts at 113l15C.

EXAMPLE II EXAMPLE III Preparation methyliodide salts (quat. ammoniumcompounds) A. Of the product obtained in example I, 2-methyl- 1,2,3,13b-tetrahydro-imida2o[3 ,4d]- dibenzo[b,f](1,4) oxazepine, 300 mg isboiled for 5 minutes in 10 ml of ether and 2 ml of methyl iodide. Themixture is cooled down, after which the precipitate obtained is filteredoff and recrystallised from ethanol. Melting point of the CH salt192l94C.

B. In the same manner the CH salt of 2,6-dimethyl-1,2,3,l3btetrahydro-imidazo[ 3,4-d]-dibenzo[b,f]( l ,4)- oxazepine(example 11.1) is prepared. Melting point of the CH salt l84-186C.

EXAMPLE IV Preparation of 12-methyl-6-chloro-1,2,3,13btetrahydro-imidazo[3,4-d]-dibenzo[b,f]( 1,4)- thiazepine and other derivatives a. 1.5 g of8-chloro-ll-methylaminomethyl-l0,l1-dihydro-dibenzo[b,f](1,4)-thiazepine are dissolved in 20 mlof ethanol,after which 10 ml of a formaldehyde solution in water are added. Themixture is heated for 40 minutes at 50C, after which it is evaporated invacuum to a volume of 15 ml. After the addition of 10 ml of water theprecipitate is filtered off and recrystallised at once from methanol.Obtained: 1.1 g of pure product; m.p. 1459147C.

b. In the same manner are prepared the 2-methylcompound (m.p. 147150C),the 2-methyl-12- chloro-compound (m.p. 1 13-1 15C) and the 2-methyl-6-trifluoro-methyl-compound 145-147C).

EXAMPLE V Preparation of 2,9-dimethyl-1 ,2,3,1 3b-tetrahydro-9H-imidazo[3,4-d]-dibenzo[b,f]( l ,4)-diazepine and other derivatives a. 8g of 5-methyl-11-methylaminomethyl-10,l1-dihydro-5l-I-dibenzo[b,e](l,4)-diazepine are added to a mixture of ml ofethanol and 25 ml of a 40% formaldehyde solution in water. The mixtureis left to stand for 30 minutes, after which it is evaporated in vacuumto one-third of the volume. Finally 40 ml of water are added and themixture is extracted with ether. The 'ether extracts are washed withwater, dried on anhydrous sodium-sulphate and evaporated. The resultingyellow oil is chromatographed over silicagel. The methanol eluateyields, after evaporation, 5.6 g of the crystalline substance, thatmelts at l02C after recrystallisation from ethanol.

b. In the same manner are prepared the 2-ethyl-9- methyl-compound (mp 98-100C) and the corresponding l2-methoxy, l2-hydroxy and 12-methylcompounds.

EXAMPLE v1 Resolution of 2-methyl- 1 ,2,3 ,1 3b-tetrahydroimidazo[3,4-d]-dibenzo[b,f](1,4)-oxazepine (racemic) 6 g of (racemic)Z-methyl-l,2,3,13b-tetrahydroimidazo[3,4-d]-dibenzo[b,f](1,4)-oxazepineare dissolved in 400 m1 of absolute ethanol. Then a solution of 2.8 g2(R), 3(R)-tartaric acid (natural tartaric acid) in 100 ml of ethanolare added. The mixture is left 'to stand overnight, after which thecrystallisate is sucked off. The crystals are passed into 1N NaOH, afterwhich the mixture is extracted with benzene. Then the benzene layer iswashed with water, dried on Na SO and evaporated to dryness. The residuehas a rotation of [04] +37.

The extraction process described above is repeated three times resultinginto a product with a constant rotation of [01],; +62; m.p. l34135C.

In the same manner the laevorotatory enantiomer is obtained with 2(8),3(5) tartaric acid (synthetic) from the mother liquors of thedextrarotatory enantiomer. [a] 62.

EXAMPLE VII Preparation of 2-m ethyl-l ,2,3 13b-tetrahydroimidazo[3,4-d]-di-benzo[b,f](1,4)-oxazepine A. Two grammesof 1l-methylaminomethyl-l0,lldihydro-dibenzo[b,f](1,4)-oxazepine aredissolved in 12 ml of methylene chloride, after which 12 mldimethylsulfoxide and 5 ml of triethylamine are added. The mixture isrefluxed for 4 hours. The excess of methylenechloride and triethylamineare distilled off in vacuo. The remaining liquid is diluted with 50 mlof water. The mixture is left to stand for one hour, after which theprecipitate, obtained after filtration, is crystallised from ethanol.The substance melts at l00102C.

B. According to the above method (reagent 111 methylenechloride) thefollowing substances are prepared:

2-methyl-12-chloro-l,2,3,13b-tetrahydroimidazo[3,4-d]-dibenzo[b,f](1,4)-thiazepine;m.p. ll2114C. 2-methyl-1,2,3,13b-tetrahydro-imidazo[3,4-d]-dibenzo[b,f](1,4)-thiazepine; m.p. 147-149C. 2,9-dimethyl-l ,2,3 ,l3b-tetrahydro-9l-I-imidazo[3,4-

d]-dibenzo[b,f](1,4)-diazepine; m.p. 102C.

EXAMPLE VIII 2-methyl-1,2,3,13b-tetrahydro-imidazo[3,4-d]-dibenzo[b,f](1,4)-oxazepine 2 g of the diamine1l-methylaminomethyl-l0,l1- dihydro-dibenzo[b,f](1,4)-oxazepine isdissolved in CS and the solution is refluxed for 6 hours. During thisrefluxing process a residue is precipitated, that is isolated byfiltration. This residue, thio-l ,2,3 ,13b-tetrahydro-imidazo[3,4-d]-dibenzo[b,f]( 1,4) oxazepine, is immediately dissolved in THF, afterwhich 1.5 g LiAlI-L, is added. The mixture is refluxed for 3 hours whilestirring. The mixture is then cooled down to 0C, after which 6 ml wateris 50 added dropwise. The mixture is stirred for one additional hour andthen filtered. The filtrate is evaporated to dry in vacuo. Afterrecrystallisation of the residue obtained from ethanol the pure compoundis obtained: m.p. 102-l03C.

The same product is obtained, if instead of CS phosgene orethylchloroformate in a suitable solvent or urea (in a melt) is used.

EXAMPLE IX l,2,3,13b-tetrahydro-imidazo[3,4-d]-dibenzo[b,f](1,4)-oxazepine In the same manner as described in example 11,2,3 ,1 3b-tetrahydroimidazo[3,4-d]-dibenzo[b,f](1,4)-oxazepine isobtaining starting from 5 dibenzo[b,f](1,4)-oxazepine.

What is claimed is: l. A compound of the formula:

in which X is oxygen, sulfur or NR in which R, is hydrogen or alkyl of1-6 carbon atoms; R and R are 20 each hydrogen, halogen, hydroxy, alkylof l-6 carbon atoms, alkoxy of 1-6 carbon atoms or trifluoromethyl; R ishydrogen, alkyl of l-6 carbon atoms or phenylalkyl of 7-10 carbon atoms;or a pharmaceutically acceptable acid addition salt or apharmaceutically acceptable quaternary ammonium compound thereof.

2. A compound according to claim 1 of the formula:

claim 1, or a pharmaceutically acceptable-acid addition salt or apharmaceutically acceptable quaternary ammonium compound thereof.

3. A compound according to claim 1 of the formula:

2-methyl-3- QN l.

ll-aminomethyl-10,l l-dihydro-

2. A compound according to claim 1 of the formula:
 3. A compoundaccording to claim 1 of the formula: 4.2,10,11-Trimethyl-1,2,3,13b-tetrahydro-imidazo-(3,4-d)-dibenzo-(b,f)(1,4)-oxazepine.